Effect of Competing Anions on Binding of Bile Salts by Cholestyramine

The binding of bile salts by cholestyramine may be influenced by other anions, as the Langmuir adsorption coefficients for three bile salts tested were similar to the model anion, citrate. However, the selectivity coefficient indicated preferential binding of cholate anion in comparison to citrate anion. Binding experiments confirmed cholestyramine's preference for bile salts as the presence of other anions reduced but did not prevent the binding of cholate anion. Binding of cholate anion was reduced in direct relationship to the citrate anion concentration. Prior exposure of cholestyramine to citrate anion caused the binding of cholate anion to decrease slightly. Sequential exposure of cholestyramine to simulated gastric fluid and simulated intestinal fluid containing cholate anion resulted in a decrease in cholate binding which was attributed to competition with anions present in the gastrointestinal fluids. Components of tomato juice and orange juice, fluids commonly used to enhance ingestion of cholestyramine, also reduced the binding of cholate anion.     

In Vitro Adsorption of Bile Salts by Colestipol Hydrochloride

The acid–base titration of colestipol hydrochloride exhibits no sharp inflection points, indicating a weakly basic anion-exchange copolymer. The swelling of colestipol hydrochloride in water and the adsorption of cholate anion are inversely related to pH and are, therefore, related to the ionization state of the copolymer. The Langmuir adsorption parameters at pH 7.5 and 37°C are similar for cholate, glycocholate, and taurocholate anions. Adsorption capacity was not related to particle size and exceeded the adsorptive capacity of the external surface by three orders of magnitude. Therefore, it is believed that the swelling of colestipol hydrochloride makes extensive internal surface area available for adsorption of bile salts. The rate of adsorption depends on the concentration of sodium cholate to which the colestipol hydrochloride is exposed. Adsorption was complete within 5 min when the concentration was below the adsorptive capacity. In contrast, adsorption at levels of sodium cholate at or above the adsorptive capacity was not complete within a 3-hr test period.     

Enteric coated insulin pellets: development, drug release and in vivo evaluation

Pellets with human insulin as a model drug were prepared by an extrusion and spheronization process to investigate the oral application of peptides. The described process proved suitable for preparing small batches of about 50 g in laboratory scale. The developed formulation was completed by the addition of aprotinin as protease inhibitor and sodium cholate as an intestinal absorption promoter to enhance oral bioavailability of insulin. In order to protect the peptide against the gastric juice the pellets were coated with shellac in a fluid-bed ball coater. Pharmaceutical properties of the produced batches were examined by analysis of contents and dissolution tests. Dissolution of insulin in simulated gastric juice of pH 1.2 was prevented by shellac. On the other hand, a rapid and complete release of the molecular-dispersed insulin from the pellets was found in simulated intestinal fluid (pH 7.5) with simultaneous efficiency of the protease inhibitor against added enzyme activity. Despite promising in vitro results no significant absorption of insulin was detected in vivo after oral application of the pellets to streptozotocin diabetic rats. High sensitivity to enzymatic degradation and low ability to cross the intestinal wall are discussed as limiting factors for the insufficient absorption of insulin in vivo.     

In vitro adsorption of mebeverine hydrochloride onto kaolin and its relationship to pharmacological effects of the drug in vivo

The in vitro uptake of mebeverine hydrochloride from an initial drug concentration of 0.25–4.25 or 0.2–3.6 g% w/v onto kaolin 5.0 g% w/v at pH 1.8 or 7.5, respectively, at 37 °C was represented by a double-layered adsorption isotherm. The calculated data were in accordance with a Langmuir adsorption isotherm for an initial drug concentration up to 2.1 or 2.0 g% w/v when a monolayer was formed at pH 1.8 or 7.5, respectively. The adsorption process is pH dependent, and is affected by the electrolyte concentration and valency. The amount of the drug desorbed (mg% w/v) by washing with different elution media at 37 °C followed the sequence 0.1 M hydrochloric acid>0.1 M magnesium chloride>0.1 M sodium chloride>simulated intestinal fluid. The results obtained from this study indicate that two mechanisms, ion exchange and physical adsorption, were involved in the uptake of mebeverine hydrochloride by kaolin. The presence of different concentrations of kaolin with the tablets or capsules of the drug, adversely affected the release rate. The in vivo and in vitro studies on guinea pig ileum showed that the presence of kaolin in a mixture with mebeverine hydrochloride did not affect to any significant level the inhibiting effect of the musculotropic drug on carbachol-induced contractions in the isolated guinea pig ileum. In vivo studies showed similar results for barium chloride as well.     

Removal of amitriptyline from simulated gastric and intestinal fluids using activated carbons

In this work, the adsorption behavior of a tricyclic antidepressant, amitriptyline hydrochloride, onto several activated carbons (ACs) is reported. The adsorption was done using in vitro simulated gastric and intestinal fluid at 37°C to test the performance of the carbons as treatment in overdose cases. The tested materials were one commercial AC (carbomix) and two ACs produced in our laboratory. The highest adsorption capacity was achieved by carbomix, followed by the laboratory-made carbons that still have a very good performance with adsorption capacity up to 120 and 100 mg/g for the gastric and intestinal fluids, respectively.     

Sorption of fluoroacetate (compound 1080) by Colestipol, activated charcoal and anion-exchange in resins in vitro and gastrointestinal decontamination in rats

The sorption of sodium fluoroacetate (FA) by activated charcoal (AC) and 5 anion exchange resins (AERs) was tested in 2 simulated gastrointestinal (GI) fluids. Each sorbent was incubated with FA in a shaker-water-bath at 37 C for 24 h. Supernatant was removed and filtered, and the concentration of FA was determined by gas chromatographic detection of the dichloroaniline derivative. Under simulated gastric conditions (0.1 M HCl at approximately pH 1.5), the sorbents removed the following proportions of FA from solution: Carbosorb AC, 87 +/- 2%; cholestyramine, 28 +/- 7%; colestipol, 96 +/- 0%; Amberlite IRA-96, 70 +/- 2%; DEAE-Sephadex, 7 +/- 4%; Chitosan, 66 +/- 2%. Under simulated intestinal conditions (0.05 M sodium phosphate at approximately pH 7.4), binding was as follows: Carbosorb AC, 68 +/- 4%; cholestyramine, 53 +/- 5%; colestipol, 46 +/- 2%; AmberliteIRA-96, 10 +/- 20%; DEAE-Sephadex, 64 +/- 7%; Chitosan, 5 +/- 2%. All findings differed significantly from control, with the exception of Amberlite IRA-96 and Chitosan in phosphate buffer, and DEAE-Sephadex in HCI. In a second study, rats were given 5 mg FA/kg, and then gavaged with 2 g/kg Carbosorb AC, colestipol or bentonite. Over 4 h, the area under the curve of serum FA versus time (AUC) decreased by 39% in the rats treated with colestipol and 42% in those treated with bentonite. In contrast, Carbosorb AC did not affect the AUC,yet increased Tmax In another study, mortality was assessed 96 h after rats were orally dosed with 5 mg FA/kg followed by gavage with 2 g/kg Carbosorb AC, colestipol or water immediatey or 30 min after dosing. When the sorbents were given immediately, mortality was the same as control (75%). Surprisingiy, the 30-min delay resulted in lower mortality in colestipol-treated rats, (approximately 38%) compared to 100% in the group treated with Carbosorb AC. Before any recommendation can be made regarding the use of colestipol as a GI decontaminant, the latter findings require confirmation in an intensive care setting. The potential for synergistic effects with 2 or more sorbents also warrant investigating.     

Novel pH-sensitive citrate cross-linked chitosan film for drug controlled release

Turbidimetric titration revealed that there were electrostatic attractive interactions between citrate and chitosan in the pH region of 4.3-7.6, depending on their degree of ionization. Citrate cross-linked chitosan film was prepared simply by dipping chitosan film into sodium citrate solution. The swelling ratio of citrate/chitosan film was sensitive to pH, ionic strength etc. Under acidic conditions, citrate/chitosan film swelled and even dissociated in the pH less than 3.5, and the model drugs (brilliant blue and riboflavin) incorporated in the film were released quickly (usually within 2 h released completely in simulated gastric fluid at 37 degrees C) while under neutral conditions the swelling ratio of citrate/chitosan film was less significant and the release rate of brilliant blue and riboflavin was low (less than 40% released in simulated intestinal fluid in 24 h). Sodium chloride weakened the electrostatic interaction between citrate and chitosan, and therefore facilitated the film swelling and accelerated drug release. The parameters of film preparation such as citrate concentration, solution pH etc. influencing the film swelling and drug release profiles were examined. The lower concentration and the higher pH of citrate solution resulted in a larger swelling ratio and quicker riboflavin release. To improve the drug controlled release properties of citrate/chitosan film, heparin, pectin and alginate were further coated on the film surface. Among them only the coating of alginate prolonged riboflavin release noticeably (for 80% of drug released the time was extended from 1.5 to 3.5 h with 0.5% w/v alginate used). The results indicated that the citrate/chitosan film was useful in drug delivery such as for the site-specific drug controlled release in stomach.     

蒙脱石散对氧氟沙星体外吸附作用研究

目的:研究蒙脱石散对氧氟沙星的体外吸附作用。方法:取不同剂量的氧氟沙星与蒙脱石散分别混合于人工胃液和人工肠液中,(37±0.5)℃水浴恒温1h后过滤,采用紫外分光光度法测定氧氟沙星的含量变化。结果:在人工胃液和人工肠液中,蒙脱石散对氧氟沙星的吸附率分别为(99.76±0.01)%和(99.55±0.02)%。结论:蒙脱石散在人工胃液和人工肠液中对氧氟沙星有强大的吸附作用,应避免同时服用2药。     

盐酸去氢骆驼蓬碱在人工胃液、肠液及蒸馏水中的稳定性考察

目的:考察盐酸去氢骆驼蓬碱在人工胃液、人工肠液及蒸馏水中的稳定性。方法:采用高效液相色谱法测定盐酸去氢骆驼蓬碱的含量,用经典恒温加速法考察温度对其在不同条件下稳定性的影响。结果:盐酸去氢骆驼蓬碱检测浓度的线性范围为1.8～30.0μg.mL-1,在人工胃液、人工肠液、蒸馏水中的降解符合一级动力学过程,预测的有效期分别为566、69、22d。结论:盐酸去氢骆驼蓬碱在人工胃液、人工肠液、蒸馏水中的稳定性均较好。     

不同pH值条件下蒙脱石散对配伍药物体外吸附作用的影响

目的研究在不同pH值人工胃液和人工肠液中蒙脱石散对常与其配伍药物诺氟沙星、氧氟沙星、萸连片、雷尼替丁、法莫替丁、阿昔洛韦、利巴韦林的体外吸附作用。方法取蒙脱石散分别加入到用不同pH人工胃液和人工肠液溶解的上述药物溶液中,用高效液相色谱法测定药物含量,计算吸附率。结果蒙脱石对萸连片中巴马汀、小檗碱的吸附率达95%以上;对诺氟沙星、氧氟沙星吸附率达80%左右;对阿昔洛韦、利巴韦林吸附率比较小,在10%以下;对法莫替丁和雷尼替丁的吸附率随着pH值的增加而降低。结论蒙脱石散对上述药物有不同的吸附作用,吸附率大的药物配伍应用时注意服药间隔时间。     

Effect of antacid magaldrate oral suspension on in-vitro and in-vivo availability of indomethacin in dogs

The adsorption of indomethacin onto Riopan and Rioplus (Magaldrate antacid oral suspension U.S.P.) was determined at 37 °C in phosphate buffer pH 7.4 and in simulated intestinal fluid U.S.P. pH 7.5. The effect of 20 ml of Riopan, given 1 h after oral administration of Indocid capsules (MSD, 25 mg) to fed dogs, on the bioavailability of indomethacin was also studied. The in-vitro study showed that the logarithm of amount of indomethacin adsorbed was linearly related to the logarithm of free drug concentration in conformity to Freundlich adsorption isotherm. The adsorptive capacities followed the sequence: Riopan (intestinal fluid) = Rioplus(intestinal fluid)>Riopan(phosphate buffer) = Rioplus (phosphate buffer). In all cases the adsorbed drug was eluted almost completely by washing with different volumes of different elution media indicating competitive physical adsorption via weak Van der Waal's attractive forces. The in-vivo study showed that the oral administration of Riopan 1 h after administration of Indocid capsules to fed dogs resulted in a significant (p < 0.05) reduction in plasma concentrations of indomethacin, a non-significant (p > 0.05) change in C_max, significantly (p < 0.05) shorter T_max and significantly reduced AUC where it decreased from 15.06 ± 5.65 to 9.52 ± 3.69 μg h/ml resulted in a relative bioavailability of 63.21% after Riopan administration.     

地龙湿法超微粉碎提取物在模拟胃肠环境中的降解研究

研究地龙湿法超微粉碎提取物在模拟胃肠环境中的降解情况。采用调整溶液pH及膜生物反应器原理两种方法终止酶解反应、Bradford法检测地龙蛋白浓度变化情况、SDS-PAGE凝胶电泳法检测地龙蛋白的降解情况、HPLC方法检测地龙小分子物质降解情况。结果表明, 地龙蛋白在人工胃液中发生完全降解; 在人工肠液中, 高分子量蛋白发生较大程度降解, 而低分子量蛋白未发现明显降解。地龙小分子物质在人工胃液中未发生明显降解; 在人工肠液中出现明显降解, 并且出现了新的小分子物质。地龙湿法超微粉碎提取物在体内发挥药效作用的物质可能是已降解后的多肽、氨基酸及可稳定存在于肠液环境的小分子物质。     

Optimization of a formulation containing viable lactic acid bacteria

In the present study, gastric juice resistant tablet formulations of lactic acid bacteria (LAB) were developed, using hydroxypropylmethylcellulose acetate succinate (HPMCAS) as well as alginates, apple pectin and Metolose as matrix forming components. To optimize the formulation-using survival rate in acid medium, and disintegration time in intestinal fluid as test parameters-tablets were modified with respect to LAB content, amount of applied excipients per tablet, and compaction forces. A decrease of viable cells of not more than one log unit after 2h of incubation in acid medium was desired, as well as a disintegration time of 1h in phosphate buffer pH 6.8. It was found that the amount of HPMCAS in the tablet correlates with gastric juice resistance. As HPMCAS also leads to a decrease of disintegration time in intestinal fluid, slight amounts of this excipient were preferred. The best protective qualities against artificial gastric juice were observed when tablets were prepared from compaction mixtures of LAB, HPMCAS and sodium alginate.     

Acceptability of cholestyramine or colestipol combinations with six vehicles

Preferences for cholestyramine or colestipol in combination with orange drink, orange juice, grape juice, apple juice, water, or apple sauce were evaluated in 40 healthy adults. Each subject evaluated the taste, texture, and smell of 30-mL samples of 12 drug-vehicle combinations (two drugs, six vehicles) using modified five-point wine-tasting scales. Samples were prepared to contain either cholestyramine 1.0 g or colestipol hydrochloride 1.3 g. The products were tested at room temperature and were administered in a random order. Subjects and observers were blinded to the identity of the products. Acceptability scores for taste, texture, and smell were significantly higher for cholestyramine than for colestipol. Total mean preference scores for cholestyramine-vehicle combinations ranged from 9.9 to 11.7; for colestipol, 6.3 to 8.9. Orange drink, apple juice, grape juice, and orange juice were the preferred vehicles for cholestyramine. The preferred vehicles for colestipol were orange drink, apple sauce, and apple juice.     

Ionotropic cross-linked chitosan microspheres for controlled release of ampicillin

The solubility of non cross-linked chitosan in weak acid solutions restricts its utility in microspheres for drug delivery. The primary aim of this study was to produce pentasodium tripolyphosphate cross-linked chitosan microspheres with higher acid resistance for controlled release of ampicillin. The microspheres were prepared by two different microencapsulation procedures (by emulsification and by spray-drying) and characterized by their particle size, surface morphology, stability, drug entrapment efficiency and drug release. The size of the microspheres was <10 microm with a narrow size distribution. The entrapment of ampicillin in the microspheres was more than 80%. Stability of uncross-linked and cross-linked microspheres was affected by the pH of simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.5). The inclusion of the enzymes pepsin and pancreatin did not affect the stability of the microspheres. The inclusion of lysozyme in phosphate buffer saline resulted in increased solubilization. The release of the drug was affected by cross-linking of microspheres with tripolyphosphate (TPP). The cross-linked microspheres were more stable in simulated gastric fluid and showed slower but sustained release of ampicillin. The antimicrobial activity of the released ampicillin was confirmed by Staphylococcus aureus bioassay.     

Interactions between ciprofloxacin and antacids--dissolution and adsorption studies

Ciprofloxacin is a fluorinated quinolone antibacterial agent extensively used against both Gram-positive and Gram-negative microorganisms. In certain polytherapy programs, ciprofloxacin can be administered with some antacids that could modify its dissolution rate and reduce its absorption leading to therapeutic failure. The aim of this study was to evaluate the influence of some antacids on the availability of ciprofloxacin. The release of ciprofloxacin from tablets in the presence of antacids, such as sodium bicarbonate, calcium hydroxide, calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, magnesium trisilicate and magaldrate was studied on BP 2002 dissolution test apparatus. These studies were carried out in simulated gastric and intestinal juices for 3 hours at 37 degrees C. The results confirmed that the dissolution rate of tablets was markedly retarded in the presence of all the antacids studied. Magaldrate and calcium carbonate in simulated gastric juice exhibited relatively higher adsorption capacities, as did magnesium trisilicate and calcium hydroxide in simulated intestinal juice.     

In-vitro interaction of a novel immunosuppressant, FK 506, and antacids.

The effect of selected antacids on the amount of FK 506 in solution in simulated gastric juice has been studied. FK 506 (2.5 mg) was incubated in 100 mL simulated gastric fluid (SGF) with the equivalent of 500 mg of various antacids. The addition of Mylanta and Tums resulted in 14 and 30% loss of FK 506, respectively, in 24 h; 98% loss was observed in 12 h in the presence of Mag-Ox; 100% loss was observed in the presence of magnesium oxide powder in 2 h. The loss of FK 506 from these solutions appears to be due to a pH mediated degradation of FK 506. The addition of aluminium hydroxide gel USP (Roxane) to the FK 506 solution resulted in a 35% loss within 2 min but no further loss was noted for 24 h, indicative of adsorption of FK 506. These results suggest that until additional in-vivo studies are carried out, it is prudent not to dose FK 506 and antacids at the same time to avoid potential interactions.     

二苯乙烯苷的体外稳定性研究

目的 研究二苯乙烯苷体外稳定性的特征.方法 采用高效液相色谱(HPLC)法测定二苯乙烯苷在模拟空腹胃液、模拟进食胃液、模拟小肠液及光照条件下的稳定性.结果 体外稳定性实验结果显示,二苯乙烯苷在模拟空腹胃液和模拟小肠液中6 h内分别降解了38.6％和49.5％,光照条件下8 h内降解了61.2％.结论 二苯乙烯苷的稳定性...     

微晶次硝酸铋对安定吸附作用的研究

用体外实验法,研究微晶次硝酸铋于人工胃液中37℃时对安定的吸附作用。微晶次硝酸铋吸附安定,符合Freundlich吸附等温式及Langmuir吸附等温式,有可能为单分子层吸附。在每次服用剂量2.5～5mg范围内,每1g微晶次硝酸铋,可吸附安定2～3.4mg,安定主要以阳离子通过静电力被吸附。被吸附的安定于人工肠液中,可进行不同程度的脱吸而再释出。     

Ranitidine Hydrochloride-loaded Ethyl Cellulose and Eudragit RS 100 Buoyant Microspheres: Effect of pH Modifiers

A floating type of dosage form of ranitidine hydrochloride in the form of microspheres capable of floating on simulated gastric fluid was prepared by solvent evaporation technique. Microspheres prepared with ethyl cellulose, Eudragit^® RS100 alone or in combination were evaluated for percent yield, drug entrapment, percent buoyancy and drug release and the results demonstrated satisfactory performance. Microspheres exhibited ranitidine hydrochloride release influenced by changing ranitidine hydrochloride-polymer and ranitidine hydrochloride-polymer-polymer ratio. Incorporation of a pH modifier has been the usual strategy employed to enhance the dissolution rate of weakly basic drug from floating microspheres. Further citric acid, fumaric acid, tartaric acid were employed as pH modifiers. Microspheres prepared with ethyl cellulose, Eudragit^® RS100 and their combination that showed highest release were utilized to study the effect of pH modifiers on ranitidine hydrochloride release from microspheres which is mainly affected due to modulation of microenvironmental pH. In vitro release of ranitidine hydrochloride from microspheres into simulated gastric fluid at 37° showed no significant burst effect. However the amount of release increased with time and significantly enhanced by pH modifiers. 15% w/w concentration of fumaric acid provide significant drug release from ranitidine hydrochloride microspheres prepared with ranitidine hydrochloride:ethyl cellulose (1:3), ranitidine hydrochloride:Eudragit^® RS100 (1:2) and ranitidine hydrochloride:ethyl cellulose:Eudragit^® RS100 (1:2:1) whereas citric acid, tartaric acid showed significant cumulative release at 20% w/w. In all this study suggest that ethyl celluose, Eudragit^® RS100 alone or in combination with added pH modifiers can be useful in floating microspheres which can be proved beneficial to enhance the bioavailability of ranitidine hydrochloride.